Synthesis of Canthin-4-ones and Isocanthin-4-ones via B Ring Construction

Canthin-4-one is synthesized via a six-step procedure starting from commercially available 3-amino-4-bromopyridine in 26% overall yield. 3-Amino-4-bromopyridine is initially converted to 8-bromo-1,5-naphthyridin-4(1H)-one. O-Methylation, intermolecular Pd-catalyzed C–C coupling, and demethylation afford the key intermediate, 8-(2-chlorophenyl)-1,5-naphthyridin-4(1H)-one, for which intramolecular C–N coupling completes the synthesis of the canthin-4-one skeleton. Ten canthin-4-one analogues were prepared in addition to the parent compound. With minor modifications, the synthesis also applies to the synthesis of two series of isocanthin-4-ones.


■ INTRODUCTION
Canthin-4-ones represent the lesser-known family of canthine alkaloids, 1 the most well-known of which are the canthin-6ones. 2 More than 60 natural analogues of canthin-6-ones have been isolated to date, but only four natural analogues of canthin-4-ones are known: tuboflavine, 3 norisotuboflavine, 4 isotuboflavine, 4 and oxoproopaline H 5 (Figure 1).The latter was only recently isolated from a mutant ΔstnK4 of Streptomyces f locculus CGMCC4, and its structure elucidated by extensive one-and two-dimensional nuclear magnetic resonance (NMR). 5everal syntheses for norisotuboflavine, 6 isotuboflavine, 7 and tuboflavine 8 have been reported.In 1966, Schmid et al. reported a four-step synthesis for tuboflavine, starting from tryptophan in 0.3% overall yield, 7 while in 1968, they reported the syntheses of norisotuboflavine and isotuboflavine, 6 in three steps starting from 4,5-dihydrocanthin-6-one in <1% overall yield.An alternative five-step synthesis for norisotuboflavine was also reported by McEvoy and Allen, starting from the natural product benzalharman with an overall yield of <1%. 6ore recently, in 2009, Bracher reported a one-step, moderateto good-yielding synthesis by reaction of carbolines with Bredereck's reagent. 9The same approach was used for the synthesis of 5-methoxycanthin-4-one, 10 which was mistakenly identified as a new alkaloid named drymaritin isolated from Drymaria diandra, 11 which was then confirmed to be the already known alkaloid cordatanine (4-methoxycanthin-6one). 12 In 2015, Bracher et al. reported two new methods for the syntheses of norisotuboflavine and tuboflavine. 13The first involved the reaction of 1-acetyl-β-carboline with either Nacetylbenzotriazole or N-propanoylbenzotriazole, which, via the in situ formation of 1,3-diketone intermediates, afforded in one step norisotuboflavine and isotuboflavine, in 34% and 16% yields, respectively.The second approach involved a four-step sequence starting from 1-bromo-β-carboline giving norisotuboflavine and isotuboflavine, in 50% and 47% yields, respectively.While these routes (Scheme 1) provided the natural products in yields higher than those of the prior syntheses, they lacked versatility.Multistep routes to synthetic canthin-4-ones starting from 9H-pyrido [3,4-b]indole-1-carbonitrile were also reported in the patent literature but with low overall yields. 14A highyielding synthesis of chiral S-(−)-5,6-dihydrocanthin-4-ones was recently reported by Batra et al. 15 While scarce, both natural and synthetic canthin-4-ones have potential in medicinal chemistry, with antimicrobial 16 and phosphodiesterase-inhibitory 14 activities reported to date.
Nevertheless, due to the lack of good general syntheses, there is limited access to structurally diverse canthin-4-one libraries, which are needed to probe structure−activity relationships.In addition, all of the known routes are based on the construction of the D ring via β-carboline precursors.
In 2017, we reported the synthesis of 3-deazacanthin-4-ones via construction of the B ring, 17 starting from 8-haloquinol-4ones using sequential Suzuki−Miyaura and C−N coupling reactions.This route allowed diversification of the A ring thanks to commercially accessible 2-halo(het)aryl boronic acids, esters, and trifluoroborates.The method was originally introduced by our group for the synthesis of canthin-6-ones. 18o apply this synthesis to canthin-4-ones, we needed access to unknown 8-bromo-1,5-naphthyridin-4(1H)-one (2) (Scheme 2).Our initial efforts to synthesize this scaffold via the thermolysis of the corresponding ylidene 1 gave only intractable tar.Herein, we report the successful thermolysis of aza-ylidene 1 and the subsequent synthesis of canthin-4ones.
Furthermore, we extend the method to structurally related isocanthin-4-ones.
The structural elucidation of side product 3 was not immediately obvious (see section S1 of the Supporting Information), but its formation suggested further dilution of the reaction mixture and/or shortening of the reaction time.After a series of trial-and-error experiments, the optimum concentration of the reaction was found, 0.03 mol/L, at ∼250 °C for 0.5 min.The reaction performed at a 1.83 mmol scale gave the desired naphthyridinone 2 in 52% yield.Attempts to improve this yield further were unsuccessful.Initial attempts to create an efficient C−C coupling at position C-8 of 8bromonaphthyridinone 2 involved the reaction of naphthyridinone 2 with 2-chlorophenylboronic acid (1.5 equiv), using two sets of conditions: (i) Pd(dppf)Cl 2 •DCM (5 mol %), K 2 CO 3 (2 equiv), and dioxane/H 2 O (75:25) or (ii) XPhos Pd G4 (2.5 mol %), K 2 CO 3 (2 equiv), and MeOH.Both sets of conditions were investigated under conventional heating or microwave (MW) irradiation, under an air or Ar atmosphere, but failed to give a complete reaction [20−30% of the starting material consumed by thin layer chromatography (TLC)].Tentatively, this was attributed to poisoning of the Pd catalyst with naphthyridinone 2 acting as a bidentate ligand to form complex 4. Complexes of Pd with bidentate ligands with a similar structural motif are reported in the literature. 19o resolve this, O-methylated analogue 5 was prepared using MeI and K 2 CO 3 in DMF (Scheme 3).Gratifyingly, the reaction of methoxynaphthyridine 5 with 2-chlorophenylboronic acid (1.5 equiv), Pd(dppf)Cl The Journal of Organic Chemistry the desired canthin-4-one 8a (76%) (18% over seven steps, starting from commercial aminopyridine).The last three steps (Suzuki coupling, demethylation, and C−N coupling) were telescoped, affording canthin-4-one 8a in an improved yield of 80% versus 54% over the three steps, and a 26% overall yield from 3-amino-4-bromopyridine.
With a successful synthesis for canthin-4-one 8a, we applied this method to synthesize isocanthin-4-ones.Translocating the nitrogen atom in the C ring can give two possible isocanthin-4ones, 9a and 10a.Of these, only isocanthin-4-one 9a and four of its derivatives have appeared in a patent. 14s in the case of canthin-4-one, the literature synthesis of isocanthin-4-one 9a involves the construction of the D ring.Fortunately, the required naphthyridinone 11 needed for the synthesis of isocanthin-4-one 9a via our approach was known. 20The Suzuki−Miyaura coupling of naphthyridinone 11 with 2-chlorophenylboronic acid, using our standard conditions, led to considerable unreacted starting material (TLC).Increasing the Pd loading from 5 to 25 mol % or performing the reaction under MW radiation 20 led to a complete reaction; however, in both cases, product 13 was obtained as a mixture with protodechlorinated 8-phenylnaphthyridinone 12, which was difficult to separate (Scheme 4).Protodechlorinated product 12 was synthesized in pure form by reaction of the naphthyridinone with phenylboronic acid, which allowed its full characterization (see section S2).Interestingly, with phenylboronic acid the reaction was performed successfully under conventional heating and 5 mol % Pd(dppf)Cl 2 •DCM giving the desired product in 71% yield.Further development of the reaction with 2-chlorophenylboronic acid was pursued using the MW conditions, owing to the lower catalyst loading and cleaner reaction mixture observed under these conditions.The C−N coupling of key intermediate 13 was also performed under MW radiation.The two-step reaction sequence, Suzuki−Miyaura coupling followed by C−N coupling, was telescoped to afford the desired isocanthin-4-one 9a in 69% yield.
The telescoped reaction was also performed on a larger scale using conventional heating conditions and an increased level of the Pd catalyst (25 mol %) to give the desired isocanthin-4-one 9a in 60% yield.
Our standard Suzuki−Miyaura coupling conditions worked well for this analogue giving a complete reaction within 10 min, without the need for MW irradiation or increased Pd loading.As in the case of naphthyridinone 11, the reaction led to a difficult to separate mixture of the desired product 17 and protodechlorinated side product 16.Performing the C−N coupling in one pot gave the desired isocanthin-4-one 10a in 77% yield (Scheme 5).
With three optimized procedures in hand for the synthesis of canthin-4-one 8a and isocanthin-4-ones 9a and 10a, a variety of 2-chlorophenylboronic acids were subjected to our optimized reaction conditions (Table 1).Sterically hindered 6-substituted (6-MeO and 6-Cl) 2-chlorophenylboronic acids failed in the Suzuki−Miyaura coupling.Both electron-releasing and -withdrawing substituents were tolerated in the synthesis of canthinones 8 and isocanthinones 10.In the synthesis of isocanthinones 9, the reaction was more sensitive to electronwithdrawing substituents, which afforded lower yields.In total, 28 new substituted analogues were prepared.

■ CONCLUSIONS
A new and efficient method for accessing canthin-4-ones via the construction of the B ring was developed.The parent canthin-4-one was prepared in six steps from commercially available 3-amino-4-bromopyridine, with the last three steps telescoped in one pot (26% overall yield).A key step was the Scheme 3. Synthesis of Canthin-4-one 8a from 8-Bromo-1,5-naphthyridin-4(1H)-one (2) a a Reagents and conditions: The Journal of Organic Chemistry synthesis of the previously unknown 8-bromo-1,5-naphthyridin-4(1H)-one (2).Suzuki−Miyaura coupling with commercially available 2-chlorophenylboronic acids followed by Cucatalyzed C−N coupling afforded the canthin-4-one skeleton.The method was general with 10 analogues prepared in good yields (35−89%).The methodology was also applied for the synthesis of two aza isomers of the canthin-4-one.In this way, a library of 19 isocanthin-4-ones was also prepared (23−88% yields).

■ EXPERIMENTAL SECTION
General Methods and Materials.All chemicals were commercially available except those whose synthesis is described.All volatiles were removed under reduced pressure.The DCM/NH 3 solvent mixture was prepared by extracting aqueous NH 4 OH (∼500 mL) with DCM (4 × 500 mL).The DCM layers were combined, dried (Na 2 SO 4 ), filtered, and stored in an amber glass bottle.Dioxane was distilled from CaH 2 before use.The combined DCM extracts were dried (Na 2 SO 4 ), filtered, and stored in a glass bottle.All microwave experiments were performed in a CEM Discover Microwave Reactor with an external surface sensor in sealed vials.For conventional heating of the reaction mixtures, aluminum heating blocks were used.All reaction mixtures and column eluents were monitored by TLC using commercial aluminum-backed TLC plates (Kieselgel 60 F 254 ).The plates were observed under ultraviolet (UV) light at 254 and 365 nm.The technique of dry flash chromatography was used throughout for all non-TLC scale chromatographic separations using silica gel 60 (<0.063 mm). 21Melting points were determined using a PolyTherm-A, Wagner & Munz, Kofler hot-stage microscope apparatus or using a TA Instruments DSC Q1000 instrument with samples hermetically sealed in aluminum pans under an argon atmosphere [using heating rates of 5 °C/min (DSC mp listed by onset and peak values)].Samples were purified by bulk recrystallization from hot, filtered saturated solutions slowly cooled to room temperature (unless otherwise stated).Recrystallization solvents are listed after melting points.UV−visible spectra were recorded using a Shimadzu UV-1900 spectrophotometer, and inflections are identified by the abbreviation "inf".Infrared spectra were recorded on a Shimadzu FTIR-NIR Prestige-21 spectrometer fitted with a Pike Miracle Ge ATR accessory, and strong, medium, and weak peaks are represented by s, m, and w, respectively. 1H and 13 C NMR spectra were recorded, as indicated, on a Bruker Avance 300 machine at 300 and 75 MHz, respectively, or on a Bruker Avance 500 machine at 500 and 125 MHz, respectively.Deuterated solvents were used for homonuclear lock, and the signals are referenced to the deuterated solvent peaks.Attached proton test (APT) NMR studies were used for the assignment of the 13 C peaks C (quaternary), CH 2 , CH 3 , and CH 4 as C (s), C (d), C (t), and C (q), respectively.Mass spectrometry data were recorded with a matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometer (positive mode) on a Bruker Autoflex III Smartbeam instrument or with the Agilent 1260 Infinity II Preparative LC/MSD System.Elemental analysis was performed using a Euro-Vector EA3000 CHN elemental analyzer.8-Bromo-1,6-naphthyridin-4(1H)-one (11) was prepared according to a literature procedure (see the Supporting Information). 20ynthesis of Meldrum's Acid Ylidenes.(7).To a solution of 4-(2-chlorophenyl)-8-methoxy-1,5-naphthyridine (6) (128.3 mg, 0.47 mmol) in dioxane (2.5 mL) was added concentrated HCl/ H 2 O (50:50) (3.6 mL), and the mixture was heated to ∼101 °C (reflux) until the starting material had been completely consumed (45 min, as determined by TLC).The mixture was left to cool to ∼20 °C, and the mixture was poured onto crushed ice, neutralized with saturated aqueous NaHCO 3 , and extracted with DCM (10 × 30 mL).The combined organic extracts were dried (Na 2 SO 4 ), filtered, evaporated to dryness, and recrystallized to give compound 7 as colorless microcrystalline powder (117.0 mg, 96%): mp (DSC) onset 265.7 °C, peak max 268.0 °C (PhCl); R f = 0.67 (82:18 DCM-NH 3 / EtOH); λ max (EtOH, nm) 244 inf (log ε = 4.30), 247 (4.31), 332 inf (4.00), 339 (4.03); v max (ATR, cm −1 ) 3362−2641w br (NH), 1622s, 1601s, 1582m, 1518s, 1477m, 1408m, 1335w, 1290m, 1202s, 1182m, 1159w, 1123w, 1107w, 1065w, 1038m, 910w, 866w, 829s, 760m, 750m; 1